Tissue-Specific Metabolic Response to Injury

对损伤的组织特异性代谢反应

• 批准号: 6794548
• 负责人: Alan J Fischman
• 金额: $ 17.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6794548
• 关键词: alanine; bioenergetics; burns; clinical research; deoxyglucose; fatty acid metabolism; glucose metabolism; glycolysis; human subject; kidney; laboratory rabbit; lactates; liver; myocardium; oxandrolone; oxygen consumption; palmitates; positron emission tomography; protein biosynthesis; striated muscles; trauma

Burn injuries produce a dramatic array of physiological and biochemical alterations, including: (1) increased energy requirements above the normal metabolic rate; (2) changes in glucose utilization and protein synthesis; (3) changes in blood flow to both the burned area and unaffected organs; and (4) increased tissue permeability at the site of trauma and in multiple other organs. Using invasive techniques, many of these processes have been studied at the organ and tissue level in animals; however, studies in humans are more limited and have involved either whole body measurements or measurements on a restricted number of organs. During the past funding cycle, using PET methods, we have developed, validated and applied new procedures for measuring blood flow, blood volume oxygen utilization and glucose metabolism in a variety of tissues and protein synthesis/degradation in skeletal muscle. Recently, we developed a device for performing some of these measurements at the bedside in critically ill patients. Using these new methods and standard techniques, the hypotheses to be evaluated in this project are: (1) There are tissue-specific energy requirements that are below normal levels in skeletal muscle but 3-4 fold higher in liver and heart. (2) Glucose is taken up into skeletal muscle at or below normal rates and undergoes anaerobic glycolysis to produce lactate alanine and little energy. (3) Protein synthesis is at or below normal levels in muscle and these rates can be modified by anaboli factors. To address these issues, we will measure: (1) regional energy metabolism in various tissues of healthy subjects and patients with burn injuries >15% BSA over the time course after injury; (2) skeletal muscle protein synthesis rates in burn patients; (3) the effects of Oxandrolone treatment on regional glucose metabolism and protein synthesis in convalescent burn patients; and (4) Glucose and fatty acid metabolism in skeletal muscle and other tissues of burned rabbits. To acquire a better understanding of the relationship between the PET measurements of glucose and fatty acid utilization and substrate oxidation, simultaneous steady-state kinetic studies of the metabolic fates of [U-14C] glucose and [1-14C] palmitate will be conducted in these burned and control rabbits.

烧伤会产生一系列显著的生理和生化变化，包括：（1） 高于正常代谢率的能量需求增加;（2）葡萄糖利用和蛋白质合成的变化;（3）流向烧伤区域和未受影响器官的血流的变化;和（4）创伤部位和多个其他器官的组织渗透性增加。使用侵入性技术，在动物的器官和组织水平上研究了许多这些过程;然而，在人类中的研究更为有限，涉及全身测量或有限数量的器官测量。在过去的资助周期中，使用PET方法，我们已经开发、验证和应用了新的程序来测量各种组织中的血流量、血容量、氧利用率和葡萄糖代谢以及骨骼肌中的蛋白质合成/降解。最近，我们开发了一种设备，用于在危重患者的床边进行这些测量。使用这些新方法和标准技术，本项目中要评估的假设是：（1）骨骼肌中存在低于正常水平但肝脏和心脏中高3-4倍的组织特异性能量需求。(2)葡萄糖以正常或低于正常的速率被骨骼肌吸收，并进行无氧糖酵解产生乳酸 丙氨酸和少量能量。(3)蛋白质的合成是在或低于正常水平的肌肉和这些速率可以修改的合成代谢因子。为了解决这些问题，我们将测量：（1）健康受试者和烧伤患者（BSA>15%）在伤后不同组织中的局部能量代谢;（2）烧伤患者骨骼肌蛋白质合成率;（3）氧甲氢龙治疗对恢复期烧伤患者局部葡萄糖代谢和蛋白质合成的影响;（4）烧伤家兔骨骼肌及其他组织中葡萄糖和脂肪酸代谢的变化。为了更好地了解葡萄糖和脂肪酸利用的PET测量值与底物氧化之间的关系，将在这些烧伤和对照家兔中同时进行[U-14 C]葡萄糖和[1- 14 C]棕榈酸酯代谢结局的稳态动力学研究。